Pharmaceutical formulation

ABSTRACT

The invention relates to pharmaceutical formulations, and more particularly to formulations containing cannabinoids for administration via a pump action spray. In particular, the invention relates to pharmaceutical formulations, for use in administration of lipophilic medicaments via mucosal surfaces, comprising: at least one lipophilic medicament, a solvent and a co-solvent, wherein the total amount of solvent and co-solvent present in the formulation is greater than 55% wt/wt of the formulation and the formulation is absent of a self emulsifying agent and/or a fluorinated propellant.

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical formulations, andmore particularly to formulations containing cannabinoids foradministration via a pump action spray.

BACKGROUND OF THE INVENTION

[0002] It has long been known to introduce drugs into the systemiccirculation system via a contiguous mucous membrane to increase onset ofactivity, potency etc.

[0003] For example, U.S. Pat. No. 3,560,625 disclose aerosolformulations for introducing an alkoxybenzamide into the systemiccirculatory system. Two different types of aerosol formulations aredisclosed:

[0004] a) fluorinated hydrocarbon type comprising 2% by weightalkoxybenzamide, 18% ethanol, and 80% propellant; and

[0005] b) nebuliser type comprising 0.5% by weight alkoxybenzamide, amixed solvent system comprising 10.3% ethanol and 31.4% propylene glycoland 57.8% deionised water.

[0006] U.S. Pat. No. 3,560,625 identifies a problem in finding asuitable solvent system to produce an aerosol spray for inhalation ofthe ortho-ethoxybenzamide, due to the fact that whilst ethanol wasundoubtedly the best solvent, a mixture containing more than 18% ofethanol by weight produced an unpleasant oral reaction which more thancounterbalanced the efficacy of the oral route.

[0007] When the present applicant set out to produce spray formulationsfor a botanical drug substance comprising one or more cannabinoids theywere aware that the highly lipophylic nature of the cannabinoids couldpresent problems in formulating the active component(s).

[0008] The present applicant first sought to develop a formulation fororomucosal, preferably sublingual, delivery in a pressurised aerosol orspray form, as disclosed in international patent applicationPCT/GB01/01027. Their initial focus was on propellant driven systemswith HFC-123a and HFC-227 but these proved to be unsuitable as solventsfor the cannabinoids. The formulations comprised synthetic Δ9-THC inamounts from 0.164 to 0.7% wt/wt, with ethanol as the primary solvent inamounts up to 20.51% by weight. One particular composition comprised0.164% synthetic Δ9-THC, 4.992% ethanol, 4.992% propylene glycol and89.582% p134a (propellant).

[0009] The applicant found that even at ethanol levels of 20% by volumeof the total formulation volume they were unable to dissolve sufficientlevels of Δ9-THC in a standard spray dose to meet clinical needs,because of the cannabinoids poor solubility in the propellant. They alsofound that the ethanol level could not be increased, as the deliverycharacteristics of the device nozzle altered substantially when thelower volatility solvents were increased above a critical ratio. TheHFC-123a and HFC-227 propellant sprays delivered a maximum of 7 mg/ml,whereas initial clinical studies suggested the formulations would berequired to contain up to 50 mg cannabinoids/ml.

[0010] Thus, the present applicants focussed on self-emulsifying drugdelivery systems, as are discussed in detail in a review articleEuropean Journal of Pharmaceutics and Biopharmaceutics 50 (2000)179-188, which concluded that the poor aqueous solubility of manychemical entities represents a real challenge for the design ofappropriate formulations aimed at enhancing oral bioavailability.

[0011] In their co-pending International application PCT/GB02/00620 theapplicant discloses a wide range of cannabinoid-containing formulationscontaining at least one self-emulsifying agent. The inclusion of atleast one self-emulsifying agent was thought necessary to get theformulation to adhere to the mucosal surface in order to achievesufficient absorption of the cannabinoids. One particular formulationcomprised 2% by wt glycerol mono-oleate, 5% CBME of G1 cannabis to giveTHC, 5% CBME of G5 cannabis to give CBD, 44% ethanol BP and 44%propylene glycol.

SUMMARY OF THE INVENTION

[0012] Surprisingly, the applicant has found that they do not absolutelyrequire the presence of a self-emulsifying agent in a liquid formulationto achieve a satisfactory dosage level by oromucosal, and specificallysub-lingual or buccal, application.

[0013] Indeed, contrary to the teachings of U.S. Pat. No. 3,560,625 andthe European Journal of Pharmaceutics and Biopharmaceutics 50 (2000)179-188, they have been able to produce a simple and effective vehiclefor delivering a lipophilic medicament in a liquid spray.

[0014] According to a specific aspect of the present invention there isprovided a pharmaceutical formulation consisting essentially of one ormore cannabinoids, ethanol and propylene glycol.

[0015] Preferably the one or more cannabinoids are present in the formof at least one extract from at least one cannabis plant. The cannabisplant(s) preferably include at least one cannabis chemovar. Mostpreferably the plant extract will be a botanical drug substance (BDS),as defined herein.

[0016] Optionally, the formulation may additionally contain a flavour,such as, for example, peppermint oil.

[0017] The formulation may also contain, in addition to thecannabinoid(s), a further active agent, which is preferably an opiate,for example morphine. Thus, it is contemplated to provide a formulationconsisting essentially of one or more cannabinoids, ethanol, propyleneglycol and an opiate, preferably morphine.

[0018] A typical liquid pharmaceutical formulation according to thisspecific aspect of the invention, given by way of example and notintended to be limiting to the invention, may contain in a 1 ml vol: THC25-50 mg/ml, preferably 25 mg/ml (based on amount of cannabinoid in abotanical drug substance), CBD 25-50 mg/ml, preferably 25 mg/ml (basedon amount of cannabinoid in a botanical drug substance), propyleneglycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml, and ethanol (anhydrous)qs to 1 ml.

[0019] Other preferred formulations include a “high THC” formulationcomprising in a 1 ml vol: THC 25 mg/ml (based on amount of cannabinoidin a botanical drug substance), propylene glycol 0.5 ml/ml, peppermintoil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml; and a “high CBD”formulation comprising in a 1 ml vol: CBD 25 mg/ml (based on amount ofcannabinoid in a botanical drug substance), propylene glycol 0.5 ml/ml,peppermint oil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml.

[0020] In these formulations the cannabinoids are added as botanicaldrug substances derived from cannabis plants, quoted amounts ofcannabinoids correspond to total amount (weight) of cannabinoid presentin 1 ml of the final formulation. The skilled reader will appreciatethat the total amount of BDS which must be added in order to achieve thedesired amount of cannabinoid in the final formulation will be dependenton the concentration of cannabinoid present in the BDS, which will varybetween different batches of BDS.

[0021] The finding that such a simple combination of one or morecannabinoids, ethanol and propylene glycol can be used effectively in apump action spray was unexpected.

[0022] The applicant has found that, where the solvent/co-solvent systemis ethanol/propylene glycol and the lipophilic medicament comprises oneor more cannabinoids in the form of a botanical drug substance (BDS),the limits in which the solvent/co-solvent will work effectively arequite narrow, as discussed below.

[0023] More broadly speaking, and according to a general aspect of theinvention, there is provided a liquid pharmaceutical formulation, foruse in administration of a lipophilic medicament via a mucosal surface,comprising at least one lipophilic medicament, a solvent and aco-solvent, wherein the total amount of solvent and co-solvent presentin the formulation is greater than 55% wt/wt of the formulation and theformulation is absent of a self-emulsifying agent and/or a fluorinatedpropellant.

[0024] Preferably the amount of solvent/co-solvent is greater than 80%,more preferably in the order 90-98%.

[0025] Preferably the formulation has a water content of less than 5%.

[0026] Preferably the formulation does not contain any type ofpropellant.

[0027] The formulation also lacks any self-emulsifying agent.Self-emulsifying agents are defined herein as an agent which will forman emulsion when presented with an alternate phase with a minimum energyrequirement. In contrast, an emulsifying agent, as opposed to aself-emulsifying agent, is one requiring additional energy to form anemulsion. Generally a self-emulsifying agent will be a soluble soap, asalt or a sulphated alcohol, especially a non-ionic surfactant or aquaternary compound. Exemplary self-emulsifying agents include, but arenot limited to, glyceryl mono oleate (esp. SE grade), glycerylmonostearate (esp. SE grade), macrogols (polyethylene glycols), andpolyoxyhydrogenated castor oils e.g. cremophor.

[0028] The formulation may additionally comprise a flavouring. Thepreferred flavouring is peppermint oil, preferably in an amount byvolume of up to 0.1%, typically 0.05% v/v.

[0029] Preferably the solvent is selected from C₁-C₄ alcohols. Thepreferred solvent is ethanol.

[0030] Preferably the co-solvent is a solvent which allows a loweramount of the “primary” solvent to be used. In combination with the“primary” solvent it should solubilise the lipophylic medicamentsufficiently that a medically useful amount of the lipophylic medicamentis solubilised. A medically useful amount will vary with the medicament,but for cannabinoids will be an amount of at least 1.0 mg/0.1 ml ofsolvent/co-solvent.

[0031] Preferred co-solvents are selected from glycols, sugar alcohols,carbonate esters and chlorinated hydrocarbons.

[0032] The glycols are preferably selected from propylene glycol andglycerol, with propylene glycol being most preferred. The carbonateester is preferably propylene carbonate.

[0033] The most preferred combination is ethanol as the solvent andpropylene glycol as the co-solvent.

[0034] The preparation of liquid formulations for oropharangeal deliveryof cannabinoids poses a number of problems. First, it is necessary todeliver at least 1.0 mg, more preferably at least 2.5 mg and even morepreferably at least 5 mg of cannabinoids per 0.1 ml of liquidformulation to achieve a therapeutic effect in a unit dose. In thisregard a patient may require up to 120 mg cannabinoid/day, on averagearound 40 mg/day to be taken in a maximum of six doses.

[0035] In the case of a sublingual or buccal delivery, this meansdelivering this quantity of the active ingredient in an amount offormulation which will not be swallowed by the patient, if the activeingredient is to be absorbed transmucosally.

[0036] Whilst such amounts can be achieved by dissolving the cannabinoidin ethanol as the solvent, high concentrations of ethanol provoke astinging sensation and are beyond the limit of tolerability.

[0037] There is thus a need to use a co-solvent in order to reduce theamount of ethanol, whilst still enabling sufficient quantities ofcannabinoid to be solubilised.

[0038] The applicant has discovered that the choice of co-solvent islimited. Preferred co-solvents should have a solubilizing effectsufficient to allow enough cannabinoid to be solubilised in a unit dose,namely at least 1.0 mg/0.1 ml of formulation, and which allows theamount of solvent present to be reduced to a level which is within thelimits of patient tolerability. Particularly suitable co-solvents whichfulfil these criteria are propylene glycol and glycerol.

[0039] In a preferred embodiment the total amount of solvent andco-solvent present in the formulation, is greater than about 65% w/w,more preferably greater than about 70% w/w, more preferably greater thanabout 75% w/w, more preferably greater than about 80% w/w, morepreferably greater than about 85% w/w of the formulation. Mostpreferably the total amount of solvent and co-solvent present in theformulation is in the range from about 80% w/w to about 98% w/w of theformulation.

[0040] In a preferred embodiment the formulations according to theinvention are liquid formulation administered via a pump-action spray.Pump-action sprays are characterised in requiring the application ofexternal pressure for actuation, for example external manual, mechanicalor electrically initiated pressure. This is in contrast to pressurizedsystems, e.g. propellant-driven aerosol sprays, where actuation istypically achieved by controlled release of pressure e.g. by controlledopening of a valve.

[0041] Pump-action sprays are found to be particularly beneficial whenit comes to delivering cannabinoids. Indeed, previously people havefocussed their attention on solvent systems including a propellant.

[0042] Whilst it has been recognised that there are disadvantages withsuch systems, including the speed of delivery, those skilled in the arthave tried to address this by slowing the propellant or by altering thenozzle. The applicants have found that by using a pump spray with theirformulations they are able to produce a spray in which the particleshave a mean aerodynamic particle size of between 15 and 45 microns, moreparticularly between 20 and 40 microns and an average of about 33microns. These contrast with particles having a mean aerodynamicparticle size of between 5 and 10 microns when delivered using apressurised system.

[0043] In fact, comparative tests by the applicant have shown such apump-action spray system to have advantages in being able to deliver theactive components to a larger surface area within the target area. Thisis illustrated with reference to the accompanying Example 3.

[0044] The variation in particle distribution and sprayed area has beendemonstrated by direct experiment. A formulation as described in theaccompanying Example 4 was filled into a pump action spray assembly(Valois vial type VP7100 actuated). The same formulation was filled intoa pressurised container powered by HFA 134a.

[0045] Both containers were discharged at a distance of 50 mm from asheet of thin paper held at right angles to the direction of travel ofthe jet. The pattern of spray produced in both cases by discharge of 100μl was then visualised against the light. In both cases the pattern ofdischarge was circular and measurements were as follows: Mean Diameter(mm) Mean Area (mm²) Pump Action Spray 23 425.5 Pressurised Spray 16201.1

[0046] The pressurised spray produced pooling of liquid at the centre ofthe area. The pump action spray gave a more even spray pattern and less“bounce back”. There was also a significantly greater area covered bythe pump action spray. The conditions under which this test was carriedout are relevant to the in-practice use of the device. A wider area ofbuccal mucosa can be reached by the pump action spray compared with thepressurised spray.

[0047] For pump spray applications the solvent/co-solvent combinationmust have a viscosity within the viscosity range defined by thepreferred solvent/co-solvent combination. Thus it should be a viscosityranging between that for an ethanol/propylene glycol combination wherethe ethanol/propylene glycol are present in the relative proportions byvolume of 60/40 and 40/60, more preferably still 55/45 to 45/55 and mostpreferably about 50/50.

[0048] The viscosity of the resulting formulation when packaged fordelivery by pump action through a mechanical pump such as, for example,a VP7 actuator valve (Valois), allows the resulting aerosol to deliver aspray having a mean aerodynamic particle size of from 20-40 microns,more preferably 25-35 and most preferably with an average particle sizeof from 30-35 microns. This maximises contact with the target mucosalmembrane for sublingual/buccal delivery.

[0049] Preferably the formulations according to the general and specificaspects of the invention comprises as the lipophilic medicament one ormore cannabinoids.

[0050] Preferably the lipophilic medicament is at least one extract fromat least one cannabis plant. The cannabis plant(s) preferably include atleast one cannabis chemovar. Most preferably the plant extract will be abotanical drug substance (BDS), as defined herein.

[0051] A “plant extract” is an extract from a plant material as definedin the Guidance for Industry Botanical Drug Products Draft Guidance,August 2000, US Department of Health and Human Services, Food and DrugAdministration Center for Drug Evaluation and Research.

[0052] “Plant material” is defined as a plant or plant part (e.g. bark,wood, leaves, stems, roots, flowers, fruits, seeds, berries or partsthereof) as well as exudates.

[0053] The term “Cannabis plant(s)” encompasses wild type Cannabissativa and also variants thereof, including cannabis chemovars whichnaturally contain different amounts of the individual cannabinoids,Cannabis sativa subspecies indica including the variants var. indica andvar. kafiristanica, Cannabis indica and also plants which are the resultof genetic crosses, self-crosses or hybrids thereof. The term “Cannabisplant material” is to be interpreted accordingly as encompassing plantmaterial derived from one or more cannabis plants. For the avoidance ofdoubt it is hereby stated that “cannabis plant material” includes driedcannabis biomass.

[0054] In the context of this application the terms “cannabis extract”or “extract from a cannabis plant”, which are used interchangeably,encompass “Botanical Drug Substances” derived from cannabis plantmaterial. A Botanical Drug Substance is defined in the Guidance forIndustry Botanical Drug Products Draft Guidance, August 2000, USDepartment of Health and Human Services, Food and Drug AdministrationCenter for Drug Evaluation and Research as: “A drug substance derivedfrom one or more plants, algae, or macroscopic fungi. It is preparedfrom botanical raw materials by one or more of the following processes:pulverisation, decoction, expression, aqueous extraction, ethanolicextraction, or other similar processes.” A botanical drug substance doesnot include a highly purified or chemically modified substance derivedfrom natural sources. Thus, in the case of cannabis, “botanical drugsubstances” derived from cannabis plants do not include highly purified,Pharmacopocial grade cannabinoids.

[0055] “Cannabis based medicine extracts (CBMEs)”, such as the CBMEsprepared using processes described in the accompanying examples, areclassified as “botanical drug substances”, according to the definitiongiven in the Guidance for Industry Botanical Drug Products DraftGuidance, August 2000, US Department of Health and Human Services, Foodand Drug Administration Center for Drug Evaluation and Research.

[0056] “Botanical drug substances” derived from cannabis plants includeprimary extracts prepared by such processes as, for example, maceration,percolation, extraction with solvents such as C1 to C5 alcohols (e.g.ethanol), Norflurane (HFA134a), HFA227 and liquid carbon dioxide undersub-critical or super-critical conditions. The primary extract may befurther purified for example by super-critical or sub-critical solventextraction, vaporisation or chromatography. When solvents such as thoselisted above are used, the resultant extract contains non-specificlipid-soluble material. This can be removed by a variety of processesincluding “winterisation”, which involves chilling to −20° C. followedby filtration to remove waxy ballast, extraction with liquid carbondioxide and by distillation.

[0057] In the case where the cannabinoids are provided as a BDS, the BDSis preferably obtained by CO₂ extraction, under sub-critical orsuper-critical conditions, followed by a secondary extraction, e.g. anethanolic precipitation, to remove a substantial proportion of waxes andother ballast. This is because the ballast includes wax esters andglycerides, unsatutrated fatty acid residues, terpenes, carotenes, andflavenoids which are not very soluble in the chosen solvent/co-solvent,particularly the preferred co-solvent, propylene glycol, and willprecipitate out. Most preferably the BDS is produced by a processcomprising decarboxylation, extraction with liquid carbon dioxide andthen a further extraction to remove significant amounts of ballast. Mostpreferably the ballast is substantially removed by an ethanolicprecipitation.

[0058] Most preferably, cannabis plant material is heated to a definedtemperature for a defined period of time in order to decarboxylatecannabinoid acids to free cannabinoids prior to extraction of the BDS.

[0059] Preferred “botanical drug substances” include those which areobtainable by using any of the methods or processes specificallydisclosed herein for preparing extracts from cannabis plant material.The extracts are preferably substantially free of waxes and othernon-specific lipid soluble material but preferably contain substantiallyall of the cannabinoids naturally present in the plant, most preferablyin substantially the same ratios in which they occur in the intactcannabis plant.

[0060] Botanical drug substances are formulated into “Botanical DrugProducts” which are defined in the Guidance for Industry Botanical DrugProducts Draft Guidance, August 2000, US Department of Health and HumanServices, Food and Drug Administration Center for Drug Evaluation andResearch as: “A botanical product that is intended for use as a drug; adrug product that is prepared from a botanical drug substance.”

[0061] “Cannabis plants” includes wild type Cannabis sativa and variantsthereof, including cannabis chemovars which naturally contain differentamounts of the individual cannabinoids.

[0062] The term “cannabinoids” also encompasses highly purified,Pharmacopoeial Grade substances, which may be obtained by purificationfrom a natural source or via synthetic means. Thus, the formulationsaccording to the invention may be used for delivery of extracts ofcannabis plants and also individual cannabinoids, or synthetic analoguesthereof, whether or not derived from cannabis plants, and alsocombinations of cannabinoids.

[0063] Preferred cannabinoids include, but are not limited to,tetrahydrocannabinoids, their precursors, alkyl (particularly propyl)analogues, cannabidiols, their precursors, alkyl (particularly propyl)analogues, and cannabinol. In a preferred embodiment the formulationsmay comprise any cannabinoids selected from tetrahydrocannabinol,Δ⁹-tetrahydrocannabinol (THC), Δ⁸-tetrahydrocannabinol,Δ⁹-tetrahydrocannabinol propyl analogue (THCV), cannabidiol (CBD),cannabidiol propyl analogue (CBDV), cannabinol (CBN), cannabichromene,cannabichromene propyl analogue and cannabigerol, or any combination oftwo or more of these cannabinoids. THCV and CBDV (propyl analogues ofTHC and CBD, respectively) are known cannabinoids which arepredominantly expressed in particular Cannabis plant varieties and ithas been found that THCV has qualitative advantageous propertiescompared with THC and CBD respectively. Subjects taking THCV report thatthe mood enhancement produced by THCV is less disturbing than thatproduced by THC. It also produces a less severe hangover.

[0064] Most preferably the formulations will contain THC and/or CBD.

[0065] In a preferred embodiment the formulations may contain specific,pre-defined ratios by weight of different cannbinoids, e.g. specificratios of CBD to THC, or tetrahydrocannabinovarin (THCV) tocannabidivarin (CBDV), or THCV to THC. Certain specific ratios ofcannabinoids have been found to be clinically useful in the treatment ormanagement of specific diseases or medical conditions. In particular,certain of such formulations have been found to be particularly usefulin the field of pain relief and appetite stimulation.

[0066] It has particularly been observed by the present applicant thatcombinations of specific cannabinoids are more beneficial than any oneof the individual cannabinoids alone. Preferred embodiments are thoseformulations in which the amount of CBD is in a greater amount by weightthan the amount of THC. Such formulations are designated as“reverse-ratio” formulations and are novel and unusual since, in thevarious varieties of medicinal and recreational Cannabis plant availableworld-wide, CBD is the minor cannabinoid component compared to THC. Inother embodiments THC and CBD or THCV and CBDV are present inapproximately equal amounts or THC or THCV are the major component andmay be up to 95.5% of the total cannabinoids present.

[0067] Preferred formulations contain THC and CBD in defined ratios byweight. The most preferred formulations contain THC and CBD in a ratioby weight in the range from 0.9:1.1 to 1.1:0.9 THC:CBD, even morepreferably the THC:CBD ratio is substantially 1:1. Other preferredformulations contain the following ratios by weight of THC andCBD:—greater than or equal to 19:1 THC:CBD, greater than or equal to19:1 CBD:THC, 4.5:1 THC:CBD, 1:4 THC:CBD and 1:2.7 THC:CBD. Forformulations wherein the THC:CBD ratio is substantially 1:1 it ispreferred that the formulation includes about 2.5 g/ml of each of THCand CBD.

[0068] Cannabis has been used medicinally for many years, and inVictorian times was a widely used component of prescription medicines.It was used as a hypnotic sedative for the treatment of “hysteria,delirium, epilepsy, nervous insomnia, migraine, pain and dysmenorrhoea”.The use of cannabis continued until the middle of the twentieth century,and its usefulness as a prescription medicine is now being re-evaluated.The discovery of specific cannabinoid receptors and new methods ofadministration have made it possible to extend the use of cannabis-basedmedicines to historic and novel indications.

[0069] The recreational use of cannabis prompted legislation whichresulted in the prohibition of its use. Historically, cannabis wasregarded by many physicians as unique; having the ability to counteractpain resistant to opioid analgesics, in conditions such as spinal cordinjury, and other forms of neuropathic pain including pain and spasm inmultiple sclerosis.

[0070] In the United States and Caribbean, cannabis grown forrecreational use has been selected so that it contains a high content oftetrahydrocannabinol (THC), at the expense of other cannabinoids. In theMerck Index (1996) other cannabinoids known to occur in cannabis such ascannabidiol and cannabinol were regarded as inactive substances.Although cannabidiol was formerly regarded as an inactive constituentthere is emerging evidence that it has pharmacological activity, whichis different from that of THC in several respects. The therapeuticeffects of cannabis cannot be satisfactorily explained just in terms ofone or the other “active” constituents.

[0071] It has been shown that tetrahydrocannabinol (THC) alone producesa lower degree of pain relief than the same quantity of THC given as anextract of cannabis. The pharmacological basis underlying thisphenomenon has been investigated. In some cases, THC and cannabidiol(CBD) have pharmacological properties of opposite effect in the samepreclinical tests, and the same effect in others. For example, in someclinical studies and from anecdotal reports there is a perception thatCBD modifies the psychoactive effects of THC. This spectrum of activityof the two cannabinoids may help to explain some of the therapeuticbenefits of cannabis grown in different regions of the world. It alsopoints to useful effects arising from combinations of THC and CBD. Thesehave been investigated by the applicant. Table 1 below shows thedifference in pharmacological properties of the two cannabinoids. TABLE1 Effect THC THCV CBD CBDV Reference CB₁ (Brain re- ++ ± Pertwee et al,1998 ceptors) CB₂ (Peripheral + − receptors) CNS Effects Anticonvulsant† −− ++ Carlini et al, 1973 Antimetrazol − − GW Data Anti-electroshock −++ GW data Muscle Relaxant −− ++ Petro, 1980 Antinociceptive ++ + GWdata Catalepsy ++ ++ GW data Psychoactive ++ − GW data Antipsychotic −++ Zuardi et al, 1991 Neuroprotective + ++ Hampson A J et al,antioxidant activity* ++ − 1998 Antiemetic + + Sedation (reduced ++Zuardi et al, 1991 spontaneous ac- tivity) Appetite stimula- ++ tionAppetite suppres- − ++ sion Anxiolytic GW data Cardiovascular EffectsBradycardia − + Smiley et al, 1976 Tachycardia + − Hypertension § + −Hypotension § − + Adams et al, 1977 Anti-inflamma- ± ± Brown, 1998 toryImmunomodula- tory/anti-inflam- matory activity Raw Paw − ++ GW dataOedema Test Cox 1 GW data Cox 2 GW data TNFα Antago- + + ++ ++ nismGlaucoma ++ +

[0072] From these pharmacological characteristics and from directexperiments carried out by the applicant it has been shown,surprisingly, that combinations of THC and CBD in varying proportionsare particularly useful in the treatment of certain therapeuticconditions. It has further been found clinically that the toxicity of amixture of THC and CBD is less than that of THC alone.

[0073] Accordingly, the invention provides pharmaceutical formulations,having all the essential features described above, which comprisecannabinoids as the active agents and which have specific ratios of CBDto THC, which have been found to be clinically useful in the treatmentor management of specific diseases or medical conditions.

[0074] In a further aspect the invention also relates to pharmaceuticalformulations having all the essential features defined above, and whichhave specific ratios of tetrahydrocannabinovarin (THCV) orcannabidivarin (CBDV). THCV and CBDV (propyl analogues of THC and CBD,respectively) are known cannabinoids which are predominantly expressedin particular Cannabis plant varieties and it has been found that THCVhas qualitative advantageous properties compared with THC and CBDrespectively. Subjects taking THCV report that the mood enhancementproduced by THCV is less disturbing than that produced by THC. It alsoproduces a less severe hangover.

[0075] The invention still further relates to pharmaceuticalformulations, having all the essential features as defined above, whichhave specific ratios of THCV to THC. Such formulations have been foundto be particularly useful in the field of pain relief and appetitestimulation.

[0076] It has particularly been observed by the present applicants thatthe combinations of the specific cannabinoids are more beneficial thanany one of the individual cannabinoids alone. Preferred embodiments arethose formulations in which the amount of CBD is in a greater amount byweight than the amount of THC. Such formulations are designated as“reverse-ratio” formulations and are novel and unusual since, in thevarious varieties of medicinal and recreational Cannabis plant availableworld-wide, CBD is the minor cannabinoid component compared to THC. Inother embodiments THC and CBD or THCV and CBDV are present inapproximately equal amounts or THC or THCV are the major component andmay be up to 95.5% of the total cannabinoids present.

[0077] Particularly preferred ratios of cannabinoids and the targetmedical conditions for which they are suitable are shown in Table 2below. Other preferred ratios of THC:CBD, THCV:CBDV and THC:TCHV andpreferred therapeutic uses of such formulations are set out in theaccompanying claims. TABLE 2 Target Therapeutic Groups for DifferentRatios of Cannabinoid Product group Ratio THC:CBD Target TherapeuticArea High THC >95:5 Cancer pain, migraine, appetite stimulation Evenratio   50:50 Multiple sclerosis, spinal cord injury, peripheral neu-ropathy, other neurogenic pain. Reverse/Broad ratio CBD <25:75Rheumatoid arthritis, Inflammatory bowel diseases. High CBD  <5:95Psychotic disorders (schizo- phrenia), Epilepsy & move- ment disordersStroke, head injury, Disease modifica- tion in RA and other inflammatoryconditions Appetite suppression

[0078] Formulations containing specific, defined ratios of cannabinoidsmay be formulated from pure cannabinoids in combination withpharmaceutical carriers and excipients which are well-known to thoseskilled in the art. Pharmaceutical grade “pure” cannabinoids may bepurchased from commercial suppliers, for example CBD and THC can bepurchased from Sigma-Aldrich Company Ltd, Fancy Road, Poole Dorset,BH124QH, or may be chemically synthesised. Alternatively, cannabinoidsmay be extracted from Cannabis plants using techniques well-known tothose skilled in the art.

[0079] In preferred embodiments of the invention the formulationscomprise extracts of one or more varieties of whole Cannabis plants,particularly Cannabis sativa, Cannabis indica or plants which are theresult of genetic crosses, self-crosses or hybrids thereof. The precisecannabinoid content of any particular cannabis variety may bequalitatively and quantitatively determined using methods well known tothose skilled in the art, such as TLC or HPLC. Thus, one may chose aCannabis variety from which to prepare an extract which will produce thedesired ratio of CBD to THC or CBDV to THCV or THCV to THC.Alternatively, extracts from two of more different varieties may bemixed or blended to produce a material with the preferred cannabinoidratio for formulating into a pharmaceutical formulation.

[0080] The preparation of convenient ratios of THC- and CBD-containingmedicines is made possible by the cultivation of specific chemovars ofcannabis. These chemovars (plants distinguished by the cannabinoidsproduced, rather than the morphological characteristics of the plant)can be been bred by a variety of plant breeding techniques which will befamiliar to a person skilled in the art. Propagation of the plants bycuttings for production material ensures that the genotype is fixed andthat each crop of plants contains the cannabinoids in substantially thesame ratio.

[0081] Furthermore, it has been found that by a process of horticulturalselection, other chemovars expressing their cannabinoid content aspredominantly tetrahydrocannabinovarin (THCV) or cannabidivarin (CBDV)can also be achieved.

[0082] Horticulturally, it is convenient to grow chemovars producingTHC, THCV, CBD and CBDV as the predominant cannabinoid from cuttings.This ensures that the genotype in each crop is identical and thequalitative formulation (the proportion of each cannabinoid in thebiomass) is the same. From these chemovars, extracts can be prepared bythe similar method of extraction. Convenient methods of preparingprimary extracts include maceration, percolation, extraction withsolvents such as C1 to C5 alcohols (ethanol), Norflurane (HFA134a),HFA227 and liquid carbon dioxide under pressure. The primary extract maybe further purified for example by supercritical or subcriticalextraction, vaporisation and chromatography. When solvents such as thoselisted above are used, the resultant extract contains non-specificlipid-soluble material or “ballast”. This can be removed by a variety ofprocesses including chilling to −20° C. followed by filtration to removewaxy ballast, extraction with liquid carbon dioxide and by distillation.Preferred plant cultivation and extract preparation methods are shown inthe Examples. The resulting extract is suitable for incorporation intopharmaceutical preparations.

[0083] There are a number of therapeutic conditions which may be treatedeffectively by cannabis, including, for example, cancer pain, migraine,appetite stimulation, multiple sclerosis, spinal cord injury, peripheralneuropathy, other neurogenic pain, rheumatoid arthritis, inflammatorybowel diseases, psychotic disorders (schizophrenia), epilepsy & movementdisorders, stroke, head injury, appetite suppression. The proportion ofdifferent cannabinoids in a given formulation determines the specifictherapeutic conditions which are best treated (as summarised in Table 2,and stated in the accompanying claims).

[0084] The principles of formulation suitable for administration ofcannabis extracts and cannabinoids can also be applied to othermedicaments such as alkaloids, bases and acids. The requirements arethat, if the medicament is insoluble in saliva, it should be solubilisedand/or brought into the appropriate unionised form by addition ofbuffering salts and pH adjustment.

[0085] Other lipophilic medicaments which may be included in the generalformulations of the invention may include, but are not limited to,morphine, pethidine, codeine, methadone, diamorphine, fentanyl,alfentanil, buprenorphine, temazepam, lipophilic analgesics and drugs ofabuse. The term “drugs of abuse” encompasses compounds which may producedependence in a human subject, typically such compounds will beanalgesics, usually opiates or synthetic derivatives thereof.

[0086] The formulation is preferably packaged in a glass vial. It ispreferably filled to a slight over-pressure in an inert atmosphere e.g.nitrogen to prevent/slow oxidative breakdown of the cannabinoids, and iscontained in a form such that ingress of light is prevented, therebypreventing photochemical degradation of the cannabinoids. This is mosteffectively achieved using an amber vial, since the applicant hasdetermined that it is UV and light in the blue spectrum, typically inthe wavelength range 200-500 nm, that is responsible forphotodegradation.

[0087] The invention will be further described, by way of example only,with reference to the following experimental data and exemplaryformulations, together with the accompanying Figures:

BRIEF DESCRIPTION OF THE DRAWINGS

[0088]FIG. 1a and 1 b illustrate mean plasma concentrations ofcannabinoids CBD, THC and 11-hydroxy THC following administration ofhigh CBD (FIG. 1a) and high THC (FIG. 1b) cannabis extracts to humansubjects.

[0089]FIG. 2 illustrates mean plasma concentrations of cannabinoids CBD,THC and 11-hydroxy THC following administration of a cannabis extractcontaining a 1:1 ratio of THC:CBD to a human subject.

[0090]FIG. 3 illustrates cross-sectional area of aerosol plume vs %propylene glycol in propylene glycol/ethanol liquid spray formulations.

[0091]FIG. 4 illustrates viscosity as a function of propylene glycolcontent in propylene glycol/ethanol liquid spray formulations.

[0092]FIG. 5 illustrates cross-sectional area of aerosol plume vsviscosity for propylene glycol/ethanol liquid spray formulations.

[0093]FIGS. 6 and 6a show results of HPLC analysis of samples drawn fromstored, light exposed solutions of THC, before and after charcoaltreatment.

[0094]FIGS. 7 and 7a show results of HPLC analysis of samples drawn fromstored, light exposed solutions of CBD, before and after charcoaltreatment.

DETAILED DESCRIPTION OF THE INVENTION

[0095] Development of Pump-Action Spray Formulations

[0096] Initially the applicant looked at cannabinoid uptake in patientsby applying drops sublingually (BDS dissolved in a mixture of aglycerol/propylene glycol and ethanol) THC 5 mg/ml, CBD 5 mg/ml andTHC/CBD 5 mg/ml plus 5 mg/ml. The results are noted in Table 3 below:TABLE 3 Initial absorption: 20 min T max: approx 2 hours C max:  6 ng/mlTHC, 2 ng/ml CBD AUC 0-12: approx 16 ng · h/ml THC, 8 ng · h/ml CBD fol-lowing a dose of approx 20 mg of each cannabinoids Plasma levels after 6hours were about 1 ng/ml THC and 0.5 ng/ml CBD

[0097] The proportion of 11 hydroxy tetrahydro cannabinol to THC(AUC0-12) was about 1.9 indicating a significant amount of oralingestion may have occurred.

[0098] On moving to a pump action sublingual spray (following problemssolubilising cannabinoids with hydroflurocabon propellant systems) theapplicant obtained the results noted in Table 4. The solvent systemcomprised 50:50 ethanol to propylene glycol (v/v ratio) with THC 25mg/ml; CBD 50 mg/ml and THC/CBD 25 mg/ml plus 50 mg/ml respectively.TABLE 4 Initial absorption: 60 min T max: approx 3 hours C max:  6 ng/mlTHC, 8 ng/ml CBD AUC 0-12: approx 16 ng · h/ml THC, 22 ng · h/ml CBDfol- lowing a dose of approx 21 mg of thc AND 35 mg CBD Plasma levelsafter 6 hours were about 1 ng/ml THC and 1 ng/ml CBD

[0099] The proportion of 11 hydroxy tetrahydro cannabinol to THC(AUC0-12) was about 1.6. The profile for each cannabinoid was similarirrespective of the formulation (THC, CBD, THC plus CBD).

[0100] After accounting for the different dosages, whilst the extent ofabsorption was comparable to the drops, the rate of absorption wasslower and the proportion metabolised reduced.

[0101] Despite the slower rate of absorption the pump spray mechanismand the ethanol/propylene glycol carrier system provided the opportunityto administer sufficient cannabinoids, in a flexible dose form withaccuracy and advantageously with reduced metabolism.

[0102] The data obtained is illustrated in FIGS. 1a, 1 b and 2, whichshow the mean plasma concentrations for the formulations identified withreference to Tables 3 and 4.

[0103] That effective delivery of the cannabinoids can be achieved in avehicle consisting of ethanol and propylene glycol is illustrated by theplasma levels shown in FIGS. 1a, 1 b and 2. These show, respectively,formulations containing the high THC and high CBD formulations in FIGS.1a and 1 b. Similarly, the effectiveness of a defined ratio formulationTHC:CBD 1:1 is illustrated in FIG. 2.

[0104] Significantly the ethanol/propylene glycol system was found toonly work with a pump action spray within quite narrow limits.

[0105] The findings giving rise to the development of pump sprayformulations, as exemplified in formulations 1-4 below, are set outbelow:

EXAMPLE 1 Significance of Particle Size

[0106] Applicant observed that the propellant aerosols that weredeveloped suffered from “bounce back” and this appeared to be a functionof delivery speed and particle size.

[0107] Applicant determined that, in contrast to the propellant drivensystem, a pump spray could deliver an aerosol plume in which theparticle size could be controlled to generate a particle size of between20 and 40 microns (thus maximising the amount of material hitting thesublingual/buccal mucosa and thus the amount of cannabinoids that can beabsorbed). To produce particles of the appropriate size the viscosity ofthe formulation needed to be carefully controlled. If the formulationwas too viscous droplet formation was hindered, a jet formed and thevalve blocked; If the formulation was not viscous enough they gotexcessive nebulisation, a plume of broad cross sectional area formed,and the spray was no longer directed solely onto the sublingual/buccalmucosa. This could result in the formulation pooling and some of theformulation being swallowed. In both cases the result is unsatisfactory.

[0108] In fact, it turned out that for the solvent of preferred choice,ethanol, and the co-solvent of preferred choice, propylene glycol, theworking range was fairly narrow as demonstrated below:

[0109] The viscosity of different combinations of ethanol/propyleneglycol were studied and their spray performance with a vp7/100 valve(Valois) compared. The results are tabulated in Table 5 below: TABLE 5Relative viscosity Propylene glycol/ethanol (run time in sec) Sprayperformance 100/0  442 Jet formed 80/20 160 Jet formed 60/40 80 Somejetting 50/50 62 Good aerosol plume 40/60 44 Good aerosol plume 20/80 26Good aerosol plume  0/100 16 Good aerosol plume

[0110] From this data it appeared that addition of propylene glycol atgreater than 60/40 would not be acceptable. These result, when readalongside U.S. Pat. No. 3,560,625, could have suggested that the saidsolvent/co-solvent combination would be no good. However, applicantfound that patients could tolerate ethanol levels of this order whenpresented in the given formulations.

[0111] The effect of viscosity on aerosol plume was quantified byspraying the various formulations at a standard distance of 0.5 cm ontodisclosing paper. The distance represents the typical distance betweenthe nozzle of the pump action spray unit and the sub lingual cavity innormal use. The paper was photocopied and the image of the plume excisedand weighed to give a relative cross sectional area. The relative valuewas then converted into a real cross sectional area by dividing thisvalue by the weight per cm² of the photocopier paper (determined byweighing a known area of paper). The results are given in Table 6 below:TABLE 6 Area of cross section of Propylene glycol/ethanol spray plume100/0   3.5 cm² 80/20 14.2 cm² 60/40 17.9 cm² 50/50 20.7 cm² 40/60 29.4cm² 20/80 54.4 cm²  0/100 93.8 cm²

[0112] This data is illustrated in FIG. 3.

[0113] Additionally plots of viscosity of mixtures of ethanol andpropylene glycol content FIG. 4 and plume cross section as a function ofviscosity FIG. 5 are given.

[0114] The figures emphasise the dramatic and undesirable changes inproperties which occur outside the narrow range of ethanol/propyleneglycol wt/wt of 60/40 and 40/60, and more particularly still 55/45 to45/55, most preferably about 50/50.

[0115] Other factors are also significant in ensuring the combination isused in a narrow range. Increasing the ethanol levels beyond 60 vol %gives rise to irritation and at propylene glycol levels approaching 60%and as low as 55%, in the case of BDS, non polar derivatives present inthe BDS begin to precipitate out on prolonged ambient storage.

[0116] Other co-solvents which might be used would be expected to havesimilar limitations. The more viscous the co-solvent the greater theproblem of producing a plume forming spray, and the more polar, thegreater the risk that precipitation will be exacerbated.

[0117] However, because the combination of ethanol/propylene glycol isable to dissolve up to 50 mg/ml (i.e. therapeutically desirable levelsof cannabinoids), is non irritating, pharmaceutically acceptable, andthe propylene glycol also acts as a penetration enhancer maximisingbioavailability of the cannabinoids it is particularly advantageous.

[0118] The mean particle size of the preferred compositions have beenshown to be 33 μm when tested using a Malvern Marsteriser. The droplets,which are considerably greater than 5 μm, therefore minimise the risk ofinhalation of aerosol.

EXAMPLE 2 Effect of Water when the Cannabinoids are Present in a BDS.

[0119] The presence of greater than 5% water in the formulation wasshown to cause precipitation of the BDS as illustrated by theinvestigation described in Table 7 below: TABLE 7 Sequential addition ofwater was made to 5 ml 25 mg/ml THC and 5 ml 25 mg/ml CBD in anethanol/propylene glycol formulate (50/50). Final Vol of water volApprox final solvent ratio % vol added ml ml Water/propyleneglycol/ethanol observation 0 5 0/50/50 Solution 0.05 5.05 1/49.5/49.5Ppt forms but redissolves on mixing 0.21 5.26 5/47.5/47.5 Ppt forms.Solution remains cloudy after mixing

[0120] Indeed because of this observation the use of anhydrous ethanolis preferred.

[0121] Example formulations (non-limiting) according to the inventionare as follows: COMPONENT AMOUNT PER UNIT (1 ml) FUNCTION COMPOSITION 1(General) Active THC (BDS) 25-50 mg/ml Active CBD (BDS) 25-50 mg/mlExcipient Propylene Glycol 0.5 ml/ml Co solvent Peppermint oil 0.0005ml/ml Flavour Ethanol (anhydrous) qs to 1 ml Solvent COMPOSITION 2 (HighTHC) Active THC (BDS) 25 mg/ml Active Excipient Propylene Glycol 0.5ml/ml Co solvent Peppermint oil 0.0005 ml/ml Flavour Ethanol (anhydrous)qs to 1 ml Solvent COMPOSITION 3 (High CBD) Active CBD (BDS) 25 mg/mlActive Excipient Propylene Glycol 0.5 ml/ml Co solvent Peppermint oil0.0005 ml/ml Flavour Ethanol (anhydrous) qs to 1 ml Solvent COMPOSITION4 (THC/CBD substantially 1:1) Active THC (BDS) 25 mg/ml Active CBD (BDS)25 mg/ml Active Excipient Propylene Glycol 0.5 ml/ml Co solventPeppermint oil 0.0005 ml/ml Flavour Ethanol (anhydrous) qs to 1 mlSolvent

EXAMPLE 3

[0122] The following example illustrates the application of liquid sprayformulations to the buccal mucosae and the blood levels produced bybuccal absorption in comparison with sublingual administration.

[0123] The following liquid formulations suitable for buccaladministration contain self-emulsifying agents, and hence do not fallwithin the scope of the present invention. Nevertheless, the generalprinciples illustrated by use of these compositions applies equally tothe delivery formulations according to the invention. Solutions wereproduced by dissolving (at a temperature not exceeding 50° C.) thefollowing ingredients (quantitative details are expressed as parts byweight):— A B C D E Glyceryl monostearate 2 — 2 — 2 (self-emulsifying)Glyceryl monooleate — 2 — 2 — (self-emulsifying) Cremophor RH40 20 30 3020 30 CBME-G1 to give THC 5 10 — — — CBME-G5 to give CBD — — 5 10 —CBME-G1 and G5 to give — — — — 10 each THC & CBD α-Tocopherol 0.1 0.10.1 0.1 0.1 Ascorbyl palmitate 0.1 0.1 0.1 0.1 0.1 Ethanol BP to produce100 100 100 100 100

[0124] Cannabis Based Medicine Extract (CBME) is an extract of cannabiswhich may be prepared by, for example, percolation with liquid carbondioxide, with the removal of ballast by cooling a concentrated ethanolicsolution to a temperature of −20° C. and removing precipitated inertplant constituents by filtration or centrifugation.

[0125] The product formed by mixing these ingredients is dispensed in 6ml quantities into a glass vial and closed with a pump action spray. Inuse, the dose is discharged through a break-up button or conventionaldesign. Proprietary devices that are suitable for this purpose are TypeVP7 produced by Valois, but similar designs are available from othermanufacturers. The vial may be enclosed in secondary packaging to allowthe spray to be directed to a particular area of buccal mucosa.Alternatively, a proprietary button with an extension may be used todirect the spray to a preferred area of buccal mucosa.

[0126] Each 1 ml of product contains 50-100 mg ofΔ⁹-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). Each actuationof the pump delivers a spray which can be directed to the buccalmucosae. In the above formulations CBMEs of known cannabinoid strengthare used. CBME-G1 is an extract from a high THC-yielding strain ofcannabis, and CBME-G5 is from a high CBD-yielding variety. It will beclear to a person skilled in the art that purified cannabinoids, andextracts containing the cannabinoids, can be made formulated asdescribed above by quantitative adjustment.

[0127] Although solutions of CBME in ethanol alone can be used as aspray, the quantity of cannabinoid that can be delivered is limited bythe aggressive nature of pure ethanol in high concentration as asolvent. This limits the amount that can be applied to the mucosaewithout producing discomfort to the patient. When a group of patientsreceived THC or CBD in a solution of the type described above, directingthe spray either sublingually or against the buccal mucosa, the patientsuniformly reported a stinging sensation with the sublingual application,but mild or no discomfort when the same solution was sprayed onto thebuccal mucosa. Spraying small quantities of this type of formulationonto the buccal mucosa does not appreciably stimulate the swallowingreflex. This provides greater dwell time for the formulation to be incontact with the buccal surface.

[0128] Formulations were administered to a group of 13 human subjects sothat they received 4 mg THC, 4 mg of CBD or placebo (vehicle alone) viaa sublingual tablet, sublingual pump-action spray or buccal route.

[0129] Absorption [area under the absorption curve (AUC)] of cannabinoidand primary metabolite were determined in samples of blood taken afterdosing. The following Table 8 gives these as normalised mean values.TABLE 8 Route of Administration PAS sublingual Sublingual tabletOropharyngeal Analyte in Plasma AUC AUC AUC THC 2158.1 1648.4 1575 11-OHTHC 3097.6 3560.5 2601.1 CBD 912 886.1 858

[0130] These results show that the total amounts of cannabinoid absorbedby sublingual and buccal (oropharyngeal) routes are similar but thatthere is a substantial (approximately 25%) reduction in the amount of11-hydroxy (11-OH) metabolite detected after oropharyngeal (buccal)administration. This finding is not inconsistent with reduced swallowing(and subsequent reduced hepatic) metabolism of the buccal formulation.

[0131] It is known that the 11-hydroxy metabolite of THC (11-OH THC) ispossibly more psychoactive than the parent compound. It is thereforedesirable to minimise the amount of this metabolite duringadministration, and this is likely to be achieved by using a formulationand method of application which reduces the amount of a buccal orsublingual dose that is swallowed. The pump action spray appears tooffer a simple means of reducing the amount of material that isswallowed and metabolised by absorption from the intestinal tract belowthe level of the oropharynx.

EXAMPLE 4 Growing of Medicinal Cannabis

[0132] Plants are grown as clones from germinated seed, under glass at atemperature of 25° C.±1.5° C. for 3 weeks in 24 hour daylight; thiskeeps the plants in a vegetative state. Flowering is induced by exposureto 12 hour day length for 8-9 weeks.

[0133] No artificial pesticides, herbicides, insecticides or fumigantsare used. Plants are grown organically, with biological control ofinsect pests.

[0134] The essential steps in production from seed accession to driedMedicinal Cannabis are summarised as follows: Seed Accessions ↓ Seedsgerminated at G-Pharm (UK) ↓ Selection for cannabinoid content andvigour ↓ Mother Plant ↓ Cuttings rooted 14-21 days in peat plug 25° C.,24 hour day length ↓ Rooted cuttings potted up in 5 litre pots ofbespoke compost ↓ Young Clone Plant established 3 weeks, 24 hour daylength, 25° C. ↓ Lower Branches Removed end of week 3 Used to make newgeneration of cuttings ↓ Induction of flowering Plant relocation to 12hour day length are to induce flowering ↓ Flower formation andmaturation 8-9 weeks at 25° C. ↓ Harvest 90% of flowers and leavessenesced ↓ Drying Under conditions of light exclusion ↓ MEDICINALCANNABIS

EXAMPLE 5 Determination of Cannabinoid Content in Plants and Extracts

[0135] Identity by TLC

[0136] a) Materials and methods

[0137] Equipment Application device capable of delivering an accuratelycontrolled volume of solution i.e., 1 μl capillary pipette or microlitre syringe.

[0138] TLC development tank with lid

[0139] Hot air blower

[0140] Silica gel G TLC plates (SIL N—HR/UV254), 200 μm layer withfluorescent indicator on polyester support.

[0141] Dipping tank for visualisation reagent.

[0142] Mobile phase 80% petroleum ether 60:80/20% Diethyl ether.

[0143] Visualisation reagent 0.1% w/v aqueous Fast Blue B (100 mg in 100ml de-ionised water). An optional method is to scan at UV 254 and 365nm.

[0144] b) Sample preparation

[0145] i) Herbal raw material

[0146] Approximately 200 mg of finely ground, dried cannabis is weighedinto a 10 ml volumetric flask. Make up to volume usingmethanol:chloroform (9:1) extraction solvent.

[0147] Extract by ultrasound for 15 minutes. Decant supernatant and usedirectly for chromatography.

[0148] ii) Herbal drug Extract

[0149] Approximately 50 mg of extract is weighed into a 25 ml volumetricflask. Make up to volume using methanol solvent. Shake vigorously todissolve and then use directly for chromatography.

[0150] c) Standards

[0151] 0.1 mg/ml delta-9-THC in methanol.

[0152] 0.1 mg/ml CBD in methanol.

[0153] The standard solutions are stored frozen at −20° C. between usesand are used for up to 12 months after initial preparation.

[0154] d) Test solutions and method

[0155] Apply to points separated by a minimum of 10 mm.

[0156] i) either 5 μl of herb extract or 1 μl of herbal extract solutionas appropriate,

[0157] ii) 10 μl of 0.1 mg/ml delta-9-THC in methanol standard solution,

[0158] iii) 10 μl of 0.1 mg/ml CBD in methanol standard solution.

[0159] Elute the TLC plate through a distance of 8 cm, then remove theplate. Allow solvent to evaporate from the plate and then repeat theelution for a second time (double development).

[0160] The plate is briefly immersed in the Fast Blue B reagent untilthe characteristic re/orange colour of cannabinoids begins to develop.The plate is removed and allowed to dry under ambient conditions in thedark.

[0161] A permanent record of the result is made either by reproductionof the image by digital scanner (preferred option) or by noting spotpositions and colours on a tracing paper.

[0162] Assay THC, THCA, CBD, CBDA and CBN by HPLC

[0163] a) Materials and methods

[0164] Equipment: HP 1100 HPLC with diode array detector andautosampler. The equipment is set up and operated in accordance within-house standard operating procedures (SOPlab037) HPLC column DiscoveryC8 5 μm, 15 × 0.46 cm plus Kingsorb ODS2 precolumn 5 μm 3 × 0.46 cm.Mobile Phase Acetonotrile:methanol:0.25% aqueous acetic acid (16:7:6 byvolume) Column Operating 25° C. Temperature Flow Rate 1.0 ml/minInjection Volume  10 μl Run time  25 mins Detection Neutral and acidcannabinoids 220 nm (band width 16 nm) Reference wavelength 400nm/bandwidth 16 nm Slit 4 nm Acid cannabinoids are routinely monitoredat 310 nm (band width 16 nm) for qualitative confirmatory andidentification purposes only. Data capture HP Chemistation with VersionA7.01 software

[0165] b) Sample preparation

[0166] Approximately 40 mg of Cannabis Based Medicinal Extract isdissolved in 25 ml methanol and this solution is diluted to 1 to 10 inmethanol. This dilution is used for chromatography.

[0167] 0.5 ml of the fill solution, contained within the Pump ActionSublingual Spray unit, is sampled by glass pipette. The solution isdiluted into a 25 ml flask and made to the mark with methanol. 200 μl ofthis solution is diluted with 800 μl of methanol.

[0168] Herb or resin samples are prepared by taking a 100 mg sample andtreating this with 5 or 10 ml of Methanol/Chloroform (9/1 w/v). Thedispersion is sonicated in a sealed tube for 10 minutes, allowed to cooland an aliquot is centrifuged and suitably diluted with methanol priorto chromatography.

[0169] c) Standards

[0170] External standardisation is used for this method. Dilution ofstock standards of THC, CBD and CBN in methanol or ethanol are made togive final working standards of approximately accurately 0.1 mg/ml. Theworking standards are stored at −20° C. and are used for up to 12 monthsafter initial preparation.

[0171] Injection of each standard is made in triplicate prior to theinjection of any test solution. At suitable intervals during theprocessing of test solutions, repeat injections of standards are made.In the absence of reliable CBDA and THCA standards, these compounds areanalysed using respectively the CBD and THC standard response factors.

[0172] The elution order has been determined as CBD, CBDA, CBN, THC andTHCA. Other cannabinoids are detected using this method and may beidentified and determined as necessary.

[0173] d) Test solutions

[0174] Diluted test solutions are made up in methanol and should containanalytes in the linear working range of 0.02-0.2 mg/ml.

[0175] e) Chromatography Acceptance Criteria:

[0176] The following acceptance criteria are applied to the results ofeach sequence as they have been found to result in adequate resolutionof all analytes (including the two most closely eluting analytes CBD andCBDA)

[0177] i) Retention time windows for each analyte:

[0178] CBD 5.4-5.9 minutes

[0179] CBN 7.9-8.7 minutes

[0180] THC 9.6-10.6 minutes

[0181] ii) Peak shape (symmetry factor according to BP method)

[0182] CBD<1.30

[0183] CBN<1.25

[0184] THC<1.35

[0185] iii) A number of modifications to the standard method have beendeveloped to deal with those samples which contain late eluting impuritypeaks e.g., method CBD2A extends the run time to 50 minutes. Allsolutions should be clarified by centrifugation before being transferredinto autosampler vials sealed with teflon faced septum seal and cap.

[0186] iv) The precolumn is critical to the quality of thechromatography and should be changed when the back pressure rises above71 bar and/or acceptance criteria regarding retention time andresolution, fall outside their specified limits.

[0187] f) Data Processing

[0188] Cannabinoids can be subdivided into neutral and acidic—thequalitative identification can be performed using the DAD dualwavelength mode. Acidic cannabinoids absorb strongly in the region of220 nm-310 nm. Neutral cannabinoids only absorb strongly in the regionof 220 nm.

[0189] Routinely, only the data recorded at 220 nm is used forquantitative analysis.

[0190] The DAD can also be set up to take UV spectral scans of eachpeak, which can then be stored in a spectral library and used foridentification purposes.

[0191] Data processing for quantitation utilises batch processingsoftware on the Hewlett Packard Chemstation.

[0192] a) Sample Chromatograms

[0193] HPLC sample chromatograms for THC and CBD Herbal Drug extractsare provided in the accompanying Figures.

EXAMPLE 6 Preparation of the Herbal Drug Extract

[0194] A flow chart showing the process of manufacture of extract fromthe High-THC and High-CBD chemovars is given below:

[0195] The resulting extract is referred to as a Cannabis Based MedicineExtract and is also classified as a Botanic Drug Substance, according tothe US Food and Drug Administration Guidance for Industry Botanical DrugProducts.

EXAMPLE 7

[0196] High THC cannabis was grown under glass at a mean temperature of21+2° C., RH 50-60%. Herb was harvested and dried at ambient roomtemperature at a RH of 40-45% in the dark. When dry, the leaf and flowerhead were stripped from stem and this dried biomass is referred to as“medicinal cannabis”.

[0197] Medicinal cannabis was reduced to a coarse powder (particlespassing through a 3 mm mesh) and packed into the chamber of aSupercritical Fluid Extractor. Packing density was 0.3 and liquid carbondioxide at a pressure of 600 bar was passed through the mass at atemperature of 35° C. Supercritical extraction is carried out for 4hours and the extract was recovered by stepwise decompression into acollection vessel. The resulting green-brown oily resinous extract isfurther purified. When dissolved in ethanol BP (2 parts) and subjectedto a temperature of −20° C. for 24 hours a deposit (consisting offat-soluble, waxy material) was thrown out of solution and was removedby filtration. Solvent was removed at low pressure in a rotaryevaporator. The resulting extract is a soft extract which containsapproximately 60% THC and approximately 6% of other cannabinoids ofwhich 1-2% is cannabidiol and the remainder is minor cannabinoidsincluding cannabinol. Quantitative yield was 9% w/w based on weight ofdry medicinal cannabis.

[0198] A high CBD chemovar was similarly treated and yielded an extractcontaining approximately 60% CBD with up to 4% tetrahydrocannabinol,within a total of other cannabinoids of 6%. Extracts were made usingTHCV and CBDV chemovars using the general method described above.

[0199] A person skilled in the art will appreciate that othercombinations of temperature and pressure (e.g. in the range +10° C. to35° C. and 60-600 bar) can be used to prepare extracts undersupercritical and subcritical conditions.

EXAMPLE 8 The Effects of Light on the Stability of the AlcoholicSolutions of THC, CBD or THCV.

[0200] The following example includes data to support the packaging ofliquid dosage forms in amber glass, to provide some protection from thedegradative effects of light on cannabinoids.

[0201] Further credence is also given to the selection of the lowestpossible storage temperature for the solutions containing cannabinoidactive ingredients.

[0202] Background and Overview:

[0203] Light is known to be an initiator of degradation reactions inmany substances, including cannabinoids. This knowledge has been used inthe selection of the packaging for liquid formulations, amber glassbeing widely used in pharmaceutical presentations as a light exclusivebarrier.

[0204] Experiments were set up to follow the effects of white light onthe stability of methanolic solutions of THC, CBD or THCV. Followingpreliminary knowledge that light of different wavelengths may havediffering effects on compound stability (viz. tretinoin is stable onlyin red light or darkness), samples were wrapped in coloured acetatefilms or in light exclusive foil. A concurrent experiment used charcoaltreated CBME to study the effects of the removal of plant pigments onthe degradation process.

[0205] Materials and Methods:

[0206] Cannabinoids: 1 mg/ml solutions of CBME were made up in ARmethanol. Methanolic solutions of CBME (100 mg/ml) were passed throughcharcoal columns (Biotage Flash 12AC 7.5 cm cartridges, b/no. 273012S)and were then diluted to 1 mg/ml. Solutions were stored in soda-glassvials, which were tightly screw capped and oversealed with stretch film.Tubes were wrapped in coloured acetate films as follows:

[0207] Red, Yellow, Green, and Cyan

[0208] Solutions were also filled into the amber glass U-save vials;these were sealed with a septum and oversealed. One tube of each seriesof samples was tightly wrapped in aluminium foil in order to completelyexclude light. This served as a “dark” control to monitor thecontribution of ambient temperature to the degradation behaviour. All ofthe above tubes were placed in a box fitted with 2×40 watt white Osramfluorescent tubes. The walls of the box were lined with reflective foiland the internal temperature was monitored at frequent intervals.

[0209] A further tube of each series was stored at −20° C. to act as apseudo to the reference sample; in addition, one tube was exposeddirectly to light without protection. Samples were withdrawn forchromatographic analysis at intervals up to 112 days following the startof the study. The study was designated AS01201/AX282.

[0210] Samples of the test solutions were withdrawn and diluted asappropriate for HPLC and TLC analysis. HPLC was carried out inaccordance with TM GE.004.V1 (SOPam058). TLC was performed on layers onSilica gel (MN SilG/UV) in accordance with TM GE.002.V1 (SOPam056).

[0211] Two further TLC systems were utilised in order to separatedegradation products:

[0212] a) SilG/UV, stationary phase, hexane/acetone 8/2 v/v mobile phase

[0213] b) RPC18 stationary phase, acetonitrile/methanol/0.25% aqueousacetic acid 16/7/6 by volume

[0214] Visualisation of cannabinoids was by Fast Blue B salt.

[0215] Results and Discussion:

[0216] HPLC Quantitative Analysis:

[0217] The results from the HPLC analysis of samples drawn from thestored, light exposed solutions, are plotted and presented as FIGS. 6and 6a (THC before and after charcoal treatment), and FIGS. 7 and 7a(CBD before and after charcoal treatment).

[0218] It can be seen from FIGS. 6 and 6a that there are significantimprovements to the stability of THC in all solutions, except thosestored in the dark (at ambient temperature) and at −20° C. (and hencewhich are not under photochemical stress). Even storage in amber glassshows an improvement when un-treated extract is compared with charcoaltreated extract. This, however, may reflect in an improvement of thethermal stability of the charcoal treated extract.

[0219]FIGS. 7 and 7a present similar data for CBD containing extracts,from which it can be seen that this cannabinoid is significantly moresensitive to the effects of light than is THC. In the absence ofcharcoal, all exposures, except in amber glass, light excluded (foil)and −20° storage, had degraded to non-detectable levels of CBD before 40days. This improved to figures of between 42 and 62 days followingcharcoal treatment. Amber glass protected CBD showed an improvement from˜38% residual compound at 112 days without charcoal clean up, toapproximately 64% at the same time after charcoal treatment. There wasalso an improvement in the stability of CBD in light excluded solutionafter charcoal treatment. This can only reflect a reduction in eitherthermo-oxidative degradation, or a residual photochemical degradationinitiated by light (and/or air) during CBME and solution preparation.

[0220] Thin Layer Chromatography Qualitative Analysis:

[0221] The evaluation of the light degraded solutions using thin layerchromatography, used both the existing normal phase system (i.e. Silicastationary phase and hexane/diethyl ether as mobile phase) and twoadditional systems, capable of resolving more polar or polymericproducts formed during the degradation processes.

[0222] Thus, chromatography using the hexane/diethyl ether system,showed that for THC by day 112, there was a reduction in the intensityof the THC and secondary CBD spots with all of the colour filteredlights (data not shown). At the same time, there was an increase in theintensity of Fast Blue B staining material running at, or close to, theorigin. Foil protected solution exhibited none of these effects.

[0223] Conclusions and Recommendations:

[0224] Cannabinoids are known to be degraded by a number of naturalchallenges, viz. light, heat, oxygen, enzymes etc. It is most likelythat in an extract of herbal plant material, which has not beensubjected to extensive clean-up procedures, that some of these processesmay still be able to continue. Paradoxically, it is also likely that theremoval of cannabinoids from the presence of any protection agentswithin the plant tissue, may render the extract more likely to sufferfrom particular degradation pathways.

[0225] Packaging into amber glass vials, conducting formulationmanufacture in amber filtered light, and the storage of plant extractsand pharmaceutical formulations at temperatures as low as possiblecompatible with manufacturing and distribution requirements and patientcompliance eliminates, or at least reduces, the effect of light ondegradation of cannabinoids. These actions dramatically improved thestorage stability of both plant extracts and finished products.

[0226] It was interesting to note that CBD appeared to be markedly lessstable than THC, when subjected to photochemical stress. This is theopposite of the finding for the relative thermo-oxidative stabilities,in which THC is the less stable. This seems to indicate that, althoughpolymeric degradation products may be the common result of bothphotochemical and thermo-oxidative degradation, the exact details of themechanism are not identical for the two processes.

[0227] Among the conclusions that can be drawn are the following:

[0228] 1] The choice of amber glass for the packaging of the dosesolutions provides improved stability, but minor improvements can bemade by additional light exclusion measures.

[0229] 2] The drying process and subsequent extraction and formulationof cannabis extracts should indeed be carried out in low intensity,amber filtered light.

[0230] 3] Consideration should be given to the blanketing of extractsunder an inert atmosphere (e.g. Nitrogen).

[0231] 4] Clean-up of cannabis extracts by simple charcoal filtrationafter winterisation, may yield substantial improvements to productshelf-life.

[0232] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein. Such equivalentsare intended to be encompassed by the following claims.

[0233] All references disclosed herein are incorporated by reference intheir entirety.

1. A liquid pharmaceutical formulation, for use in administration of alipophilic medicament via a mucosal surface, comprising: at least onelipophilic medicament, a solvent and a co-solvent, wherein the totalamount of solvent and co-solvent present in the formulation is greaterthan 55% wt/wt of the formulation and the formulation is absent of aself emulsifying agent and/or a fluorinated propellant.
 2. A liquidpharmaceutical formulation as claimed in claim 1 with a water content ofless than 5%.
 3. A liquid pharmaceutical formulation as claimed in claim1 or 2 wherein the solvent is selected from C1-C4 alcohols.
 4. A liquidpharmaceutical formulation as claimed in claim 3 wherein the solvent isethanol.
 5. A liquid pharmaceutical formulation as claimed in any of thepreceding claims wherein the co-solvent is selected from glycols, sugaralcohols, carbonate esters and chlorinated hydrocarbons.
 6. A liquidpharmaceutical formulation as claimed in claim 5 wherein the glycols areselected from propylene glycol and glycerol, and the carbonate ester ispropylene carbonate.
 7. A liquid pharmaceutical formulation as claimedin claim 5 wherein the co-solvent is propylene glycol.
 8. A liquidpharmaceutical formulation as claimed in claim 1 or 2 wherein thesolvent is ethanol and the co-solvent is propylene glycol.
 9. A liquidpharmaceutical formulation as claimed in claim 8 whereinethanol/propylene glycol are present in relative proportions by weightin the range 60/40 to 40/60.
 10. A liquid pharmaceutical formulation asclaimed in claim 8 wherein ethanol/propylene glycol are present inrelative proportions by weight in the range 55/45 to 45/55.
 11. A liquidpharmaceutical formulation as claimed in claim 8 whereinethanol/propylene glycol are present in the relative proportions byweight of about 50/50.
 12. A liquid pharmaceutical formulation asclaimed in any of the preceding claims further comprising a flavouring.13. A liquid pharmaceutical formulation as claimed in claim 12 whereinthe flavouring is peppermint oil.
 14. A liquid pharmaceuticalformulation as claimed in claim 12 or claim 13 wherein the flavouring ispresent in an amount up to 0.1% v/v, preferably 0.05% v/v.
 15. A liquidpharmaceutical formulation as claimed in any of the preceding claimswherein the lipophilic medicament comprises one or more cannabinoids.16. A liquid pharmaceutical formulation as claimed in claim 15 whereinthe lipophilic medicament is at least one extract from at least onecannabis plant.
 17. A liquid pharmaceutical formulation as claimed inclaim 16 wherein the extract from at least one cannabis plant is abotanical drug substance.
 18. A liquid pharmaceutical formulation asclaimed in claim 17 wherein the botanical drug substance has undergonean extraction step to remove a substantial proportion of waxes and othersolvent insoluble materials present in plant material.
 19. A liquidpharmaceutical formulation as claimed in claim 17 or 18 wherein thebotanical drug substance is a CO₂ extract of one or more cannibisplants.
 20. A liquid pharmaceutical formulation as claimed in any of onethe preceding claims consisting essentially of one or more cannabinoids,ethanol and propylene glycol, and optionally a flavouring and/or anopiate.
 21. A liquid pharmaceutical formulation wherein the lipophilicmedicament comprises tetrahydrocannabinol, Δ9-tetrahydrocannabinol,Δ⁸-tetrahydrocannabinol, Δ⁹-tetrahydrocannabinol propyl analogue,cannabidiol, cannabidiol propyl analogue, cannabinol, cannabichromene,cannabichromene propyl analogue, cannabigerol or any mixture thereof.22. A liquid pharmaceutical formulation as claimed in any one of claims15 to 21 wherein the cannabinoids include THC and/or CBD.
 23. A liquidpharmaceutical formulation as claimed in claim 22 wherein THC and CBDare present in a ratio (w/w) of from 0.9:1.1 to 1.1:0.9.
 24. A liquidpharmaceutical formulation as claimed in claim 22 wherein THC and CBDare present in a ratio (w/w) of about 1:1.
 25. A liquid pharmaceuticalformulation according to claim 24 which formulation includes 2.5 g/ml ofeach of THC and CBD.
 26. A liquid pharmaceutical formulation as claimedin any one of claims 15 to 21 which comprises both the cannabinoidscannabidiol (CBD) and tetrahydrocannabinol (THC), or the cannabinoidstetrahydrocannabinovarin (THCV) and cannabidivarin (CBDV), in apre-defined ratio by weight.
 27. A liquid pharmaceutical formulationaccording to claim 26 which comprises both the cannabinoids cannabidiol(CBD) and tetrahydrocannabinol (THC), wherein the CBD is present in anamount by weight which is greater than the amount by weight of THC. 28.A liquid pharmaceutical formulation according to claim 27 wherein theratio by weight of CBD to THC is greater than 2.5:1.
 29. A liquidpharmaceutical formulation according to claim 27 or claim 28 wherein theratio by weight of CBD to THC is between 99:1 and 2.5:1, preferablybetween about 20:1 and about 2.5:1.
 30. A liquid pharmaceuticalformulation according to any one of claims 27 to 29 wherein the ratio byweight of CBD to THC is about 19:1.
 31. A liquid pharmaceuticalformulation according to any one of claims 27 to 29 wherein the ratio byweight of CBD to THC is in the range from about 5:1 to about 3:1.
 32. Aliquid pharmaceutical formulation according to any one of claims 27 to31 which is substantially free of cannabinoids other than CBD and THC.33. A liquid pharmaceutical formulation according to claim 32 which issubstantially free of other cannabinoids found in Cannabis sp.
 34. Aliquid pharmaceutical formulation according to any one of claims 27 to33 wherein the CBD and THC are in substantially pure form.
 35. A liquidpharmaceutical formulation according to any one of claims 27 to 31 whichfurther comprises one or more other cannabinoids.
 36. A liquidpharmaceutical formulation according to claim 35 wherein the one or moreother cannabinoids are tetrahydrocannabinovarin (THCV) and/orcannabidivarin (CBDV).
 37. A liquid pharmaceutical formulation accordingto any one of claims 27 to 31, 35 or 36 wherein the CBD and THC formpart of least one extract from at least one Cannabis plant, said atleast one extract comprising all the naturally occurring cannabinoids insaid plant.
 38. A liquid pharmaceutical formulation according to claim37 wherein the Cannabis plant is selected from Cannabis sativa, Cannabisindica, a genetic cross between them, a self-cross or a hybrid thereof.39. A liquid pharmaceutical formulation according to claim 38 whereinthe Cannabis plant is Cannabis sativa, subspecies indica and is selectedfrom var. indica and var. kafiristanica.
 40. A liquid pharmaceuticalformulation as claimed in any one of claims 37 to 39 which comprisesextracts from two or more different Cannabis varieties wherein in thefinal formulation the amount of CBD is greater than the amount of THC byweight.
 41. A liquid pharmaceutical formulation according to any one ofclaims 37 to 39 wherein said extract is prepared by supercritical orsub-critical fluid extraction of dried Cannabis plant.
 42. A liquidpharmaceutical formulation according to claim 26 which comprises boththe cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC),wherein the THC is present in an amount by weight which is greater thanthe amount by weight of CBD.
 43. A liquid pharmaceutical formulationaccording to claim 42 wherein the pre-defined ratio by weight of CBD toTHC is between 1:99 and 1:1.5.
 44. A liquid pharmaceutical formulationaccording to claim 43 wherein said pre-defined ratio by weight of CBD toTHC is about 1:39.
 45. A liquid pharmaceutical formulation according toclaim 43 wherein said pre-defined ratio by weight of CBD to THC is about1:2.
 46. A liquid pharmaceutical formulation according to claim 26 whichcomprises both the cannabinoids tetrahydrocannabinovarin (THCV) andcannabidivarin (CBDV) wherein the CBDV is present in an amount by weightwhich is greater than the amount by weight of THCV.
 47. A liquidpharmaceutical formulation according to claim 46 which further comprisesCBD and/or THC.
 48. A liquid pharmaceutical formulation according toclaim 46 or 47 wherein the ratio by weight of CBDV to THCV is greaterthan 1.5:1.
 49. A liquid pharmaceutical formulation according to any oneof claims 46 to 48 wherein the ratio by weight of CBDV to THCV is in therange from about 99:1 to about 1.5:1, preferably from about 20:1 toabout 2.5:1.
 50. A liquid pharmaceutical formulation according to anyone of claims 46 to 49 wherein the ratio by weight of CBDV to THCV isabout 9:1.
 51. A liquid pharmaceutical formulation according to any oneof claims 46 to 49 wherein the ratio of CBDV to THCV by weight is fromabout 5:1 to 3:1.
 52. A liquid pharmaceutical formulation according toclaim 46 or any one of claims 48 to 51 which is substantially free fromother cannabinoids found in Cannabis sp.
 53. A liquid pharmaceuticalformulation according to any one of claims 46 to 52 wherein the CBDV andTHCV form part of an extract from a Cannabis plant, said extractcomprising all of the naturally occurring cannabinoids in said plant.54. A liquid pharmaceutical formulation according to claim 53 whereinthe Cannabis plant is selected from Cannabis sativa, Cannabis indica ora genetic cross between them, a self-cross or a hybrid thereof.
 55. Aliquid pharmaceutical formulation as claimed in any one of claims 15 to21 which comprises both the cannabinoids THC and THCV wherein the THCVis present in an amount by weight which is approximately equal to orgreater than the amount by weight of THC.
 56. A liquid pharmaceuticalformulation according to claim 55 wherein the ratio by weight of THCV toTHC is between 99:1 and 1.5:1.
 57. A liquid pharmaceutical formulationaccording to claim 55 or 56 wherein the ratio by weight of THCV to THCis approximately 17:3.
 58. A liquid pharmaceutical formulation accordingto any one of claims 55 to 57 which also comprises CBD and/or CBDV at anamount by weight which is less than the amount by weight of THCV.
 59. Aliquid pharmaceutical formulation according to any one of claims 55 to58 wherein the THCV and THC form part of an extract from a Cannabisplant, said extract comprising all the naturally occurring cannabinoidsin said plant.
 60. A liquid pharmaceutical formulation according toclaim 59 wherein said Cannabis plant is selected from Cannabis sativa,Cannabis indica or the result of a genetic cross between them, aself-cross or a hybrid thereof.
 61. A liquid pharmaceutical formulationaccording to any one of claims 26 to 42, 46 to 59 for use in thetreatment of inflammatory disease or any disease or condition during thecourse of which oxidative stress plays a part.
 62. A liquidpharmaceutical formulation according to claim 32 or 51 for use in thetreatment of rheumatoid arthritis, or inflammatory bowel disease orCrohn's disease.
 63. A liquid pharmaceutical formulation according toclaim 31 or 50 for use in the treatment of psychotic disorders,epilepsy, movement disorders, stroke, head injury, or diseases whichrequire appetite suppression.
 64. A liquid pharmaceutical formulationaccording to any one of claims 15 to 21 which comprises approximatelyequal amounts of CBD and THC or THCV and CBDV for the treatment ofmultiple sclerosis, spinal cord injury, peripheral neuropathy or otherneurogenic pain.
 65. A liquid pharmaceutical formulation according toany one of claims 15 to 21 which comprises a ratio by weight of THC toCBD or THCV to CBDV of from about 39:1 to about 99:1 for use in thetreatment of cancer pain or migraine or for stimulation of appetite. 66.A liquid pharmaceutical formulation for use according to claim 65wherein the ratio by weight of THC to CBD or THCV to CBDV isapproximately 39:1.
 67. A liquid pharmaceutical formulation for useaccording to claim 65 or 66 wherein in the formulation the THC and CBDand/or THCV and CBDV form part of an extract from a Cannabis plant, saidextract comprising all the naturally occurring cannabinoids in saidplant.
 68. A liquid pharmaceutical formulation comprising in a 1 ml vol:THC 25 mg/ml (based on amount of cannabinoid in a botanical drugsubstance), CBD 25 mg/ml (based on amount of cannabinoid in a botanicaldrug substance), propylene glycol 0.5 ml/ml, peppermint oil 0.0005ml/ml, and ethanol (anhydrous) qs to 1 ml.
 69. A liquid pharmaceuticalformulation comprising in a 1 ml vol: THC 25 mg/ml (based on amount ofcannabinoid in a botanical drug substance), propylene glycol 0.5 ml/ml,peppermint oil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml.
 70. Aliquid pharmaceutical formulation comprising in a 1 ml vol: CBD 25 mg/ml(based on amount of cannabinoid in a botanical drug substance),propylene glycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml, and ethanol(anhydrous) qs to 1 ml.
 71. A liquid pharmaceutical formulation asclaimed in any of claims 1 to 14 wherein the lipophilic medicament isselected from: morphine, pethidine, codeine, methadone, diamorphine,fentanyl, alfentanil, temazepam, buprenorphine, lipophilic analgesicsand drugs of abuse.
 72. A liquid pharmaceutical formulation as claimedin any of the preceding claims which is packaged for delivery as a sprayhaving a mean aerodynamic particle size, when delivered, of from 20-40microns, more preferably 25-35 and most preferably 30-35 microns.
 73. Aliquid pharmaceutical formulations as claimed in claim 72 which ispackaged for delivery as a pump-action spray.
 74. A liquidpharmaceutical formulation as claimed in claim 73 wherein theformulation is dispensed through a mechanical pump.
 75. A liquidpharmaceutical formulation as claimed in claim 74 wherein the mechanicalpump comprises a VP7 actuator valve.
 76. A liquid pharmaceuticalformulation as claimed in any of the preceding claim wherein theformulation is packaged in a container coloured to omit UV light andlight from the blue region of the spectrum, preferably at wavelengths inthe range of 200-500 nm.
 77. A liquid pharmaceutical formulation asclaimed in claim 76 wherein the container is coloured amber.
 78. Aliquid pharmaceutical formulation as claimed in any of the precedingclaims wherein the lipophilic medicament is packaged in an inertatmosphere.
 79. A liquid pharmaceutical formulation as claimed in claim78 wherein the lipophilic medicament is packaged under nitrogen.